The genetic architecture of breast papillary lesions as a predictor of progression to carcinoma

Tanjina Kader,Simone M Rowley,Stephen B Fox,Kenneth Elder,Jia-Min Pang,Magnus Zethoven,Timothy Semple,Emad A Rakha,Dane Cheasley,Ian G Campbell,G Bruce Mann,Prue Hill,Kylie L Gorringe,Andrew R Green,Islam M Miligy,David L Goode,David J Byrne,Niko Thio

doi:10.1038/s41523-020-0150-6

Abstract

Intraductal papillomas (IDP) are challenging breast findings because of their variable risk of progression to malignancy. The molecular events driving IDP development and genomic features of malignant progression are poorly understood. In this study, genome-wide CNA and/or targeted mutation analysis was performed on 44 cases of IDP, of which 20 cases had coexisting ductal carcinoma in situ (DCIS), papillary DCIS or invasive ductal carcinoma (IDC). CNA were rare in pure IDP, but 69% carried an activating PIK3CA mutation. Among the synchronous IDP cases, 55% (11/20) were clonally related to the synchronous DCIS and/or IDC, only one of which had papillary histology. In contrast to pure IDP, PIK3CA mutations were absent from clonal cases. CNAs in any of chromosomes 1, 16 or 11 were significantly enriched in clonal IDP lesions compared to pure and non-clonal IDP. The observation that 55% of IDP are clonal to DCIS/IDC indicates that IDP can be a direct precursor for breast carcinoma, not limited to the papillary type. The absence of PIK3CA mutations and presence of CNAs in IDP could be used clinically to identify patients at high risk of progression to carcinoma.

Highlights

Intraductal breast papilloma (IDP) is characterised by a continuous myoepithelial cell layer with the presence of fibro-vascular papillary stalks and the ductal epithelium[1]
Sample characteristics and architectural features of pure papilloma cases All pure IDP cases (IDP without coexisting carcinoma) (n = 24, Supplementary File 1) were ER+ with a mosaic staining in benign cases but diffuse strong nuclear staining seen in areas with atypia. p63 staining to highlight the myoepithelial cells at the epithelialstroma interface, which is commonly used to confirm a diagnosis of IDP, was present in all cases
We find that the absence of CN events, regardless of histopathological subtype, symptoms or age of the patient, is strongly associated with lack of progression potential, raising the possibility that IDP showing no CN events could be spared from routine surgical excision

Summary

Introduction

Intraductal breast papilloma (IDP) is characterised by a continuous myoepithelial cell layer with the presence of fibro-vascular papillary stalks and the ductal epithelium[1]. Focused somatic mutation studies have showed a high prevalence of PIK3CA mutations and AKT1 pathway activation in both benign and atypical IDP12,13, but interestingly not in papillary carcinoma (PC). These findings raise a question about where IDP fits in the breast cancer progression pathway. A diagnosis of IDP carries an increased risk of developing breast cancer, it has long been suggested that IDP could only directly progress to PC It is still inexplicable why IDP has been observed to co-exist with the more common non-papillary forms of ductal carcinoma in situ (DCIS)/ invasive ductal carcinoma (IDC)[14,15,16,17,18]

Methods

Results

Conclusion